U.S. patent application number 17/457248 was filed with the patent office on 2022-03-24 for injectable sustained release composition and method of using the same for treating inflammation in joints and pain associated therewith.
The applicant listed for this patent is Eupraxia Pharmaceuticals USA LLC. Invention is credited to Marc M. Baum, James A. Helliwell, Amanda M. Malone, Thomas J. Smith.
Application Number | 20220087943 17/457248 |
Document ID | / |
Family ID | |
Filed Date | 2022-03-24 |
United States Patent
Application |
20220087943 |
Kind Code |
A1 |
Helliwell; James A. ; et
al. |
March 24, 2022 |
INJECTABLE SUSTAINED RELEASE COMPOSITION AND METHOD OF USING THE
SAME FOR TREATING INFLAMMATION IN JOINTS AND PAIN ASSOCIATED
THEREWITH
Abstract
Described herein are injectable corticosteroid-loaded
microparticles, pharmaceutical composition thereof and methods for
reducing inflammation or pain in a body compartment such as a
joint, an epidural space, a vitreous body of an eye, a surgically
created space, or a space adjacent to an implant.
Inventors: |
Helliwell; James A.;
(Victoria, CA) ; Malone; Amanda M.; (Victoria,
CA) ; Smith; Thomas J.; (Santa Monica, CA) ;
Baum; Marc M.; (Pasadena, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Eupraxia Pharmaceuticals USA LLC |
Victoria |
|
CA |
|
|
Appl. No.: |
17/457248 |
Filed: |
December 1, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15975577 |
May 9, 2018 |
11219604 |
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17457248 |
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14222082 |
Mar 21, 2014 |
9987233 |
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15975577 |
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61804185 |
Mar 21, 2013 |
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International
Class: |
A61K 9/50 20060101
A61K009/50; A61K 31/56 20060101 A61K031/56; A61K 31/58 20060101
A61K031/58; A61K 9/00 20060101 A61K009/00 |
Claims
1. A unit dosage form comprising: a plurality of microparticles,
the microparticle including: (1) a crystalline drug core of more
than 70% by weight of the microparticle; and (2) a polymeric shell
encapsulating the crystalline drug core, wherein the crystalline
drug core includes one or more crystals of a corticosteroid
selected from fluticasone, fluticasone furoate, and fluticasone
propionate, and the polymeric shell is in contact but immiscible
with the crystalline drug core; and wherein the unit dosage form
releases the corticosteroid over a period of 2-12 months while
maintaining a minimum therapeutically effective concentration of
the corticosteroid within a body compartment.
2. The unit dosage form according to claim 1 wherein the body
compartment is a joint, an epidural space, intravitreal space, a
surgically created space, or a space adjacent to an implant.
3. The unit dosage form according to claim 1 wherein, within the
sustained release period of 2-12 months, the corticosteroid is
released locally within the body compartment and provides below a
quantifiable limit of plasma corticosteroid 7 days after
injection.
4. The unit dosage form according to claim 1 wherein the plurality
of microparticles have a mean diameter in the range of 50 .mu.m to
150 .mu.m and a standard deviation of less than 50% of the mean
diameter.
5. The unit dosage form according to claim 1 wherein the
microparticle comprises 90-98% w/w of crystalline drug core and
2-10% w/w of polymeric shell.
6. The unit dosage form according to claim 1 wherein the polymeric
shell comprises one or more biodegradable polymers selected from
the group consisting of polyvinyl alcohol (PVA), ethylene vinyl
acetate (EVA), poly(p-xylylene) polymers, poly(lactic acid) (PLA),
poly(glycolic acid) (PGA), poly(lactic-co-glycolic acid) (PLGA),
poly( -caprolactone) (PCL), poly(valerolactone) (PVL), poly(
-decalactone) (PDL), poly(1,4-dioxane-2,3-dione),
poly(1,3-dioxane-2-one), poly(para-dioxanone) (PDS),
poly(hydroxybutyric acid) (PHB), poly(hydroxyvaleric acid) (PHV),
and poly(.beta.-malic acid) (PMLA).
7. An extended release formulation comprising a plurality of
microparticles having core/shell morphology, wherein the
microparticle includes (1) a crystalline drug core of more than 70%
by weight of the microparticle, wherein the crystalline drug core
includes one or more crystals of a corticosteroid, a salt or ester
thereof; and (2) a polymeric shell encapsulating the crystalline
drug core, whereby the polymeric shell is in contact but immiscible
with the crystalline drug core.
8. The extended release formulation according to claim 7, wherein
the corticosteroid is selected from fluticasone, fluticasone
furoate, and fluticasone propionate.
9. The extended release formulation according to claim 8, wherein
the polymeric shell comprises one or more of the polymers selected
from the group consisting of polyvinyl alcohol (PVA),
poly(p-xylylene) polymers (trademarked as Parylene.RTM.),
poly(lactic acid) (PLA), poly(glycolic acid) (PGA),
poly(lactic-co-glycolic acid) (PLGA), poly( -caprolactone) (PCL),
poly(valerolactone) (PVL), poly( -decalactone) (PDL),
poly(1,4-dioxane-2,3-dione), poly(1,3-dioxane-2-one),
poly(para-dioxanone) (PDS), poly(hydroxybutyric acid) (PHB),
poly(hydroxyvaleric acid) (PHV), ethylene vinyl acetate (EVA) and
poly(.beta.-malic acid) (PM LA).
10. The extended release formulation according to claim 7 wherein
said microparticles have a mean diameter of between 50 .mu.m and
400 .mu.m.
11. The pharmaceutical composition according to claim 7 wherein
said microparticles have a mean diameter of between 80 .mu.m and
150 .mu.m.
12. A method for treating inflammation or pain in a patient in need
thereof, the method comprising administering to the patient the
extended release formulation of claim 7.
13. The method according to claim 12, wherein the inflammation or
pain is due to at least one of osteoarthritis, rheumatoid arthritis
or injury induced arthritis, spinal disc protrusion, spinal nerve
inflammation in cervical, thoracic or lumbar, chronic low back pain
from nerve root compression, diabetic macular edema or uveitis,
recurrent capsular contractions or keloid scarring.
14. The method according to claim 12 wherein administering the
extended release formulation comprises locally injecting to an
affected joint, an epidural space, vitreous body, an epidural
space, or a space adjacent to an implant having scar tissue of said
patient.
15. The method according to claim 14 wherein the corticosteroid is
released locally within the body compartment and provides below a
quantifiable limit of plasma corticosteroid 7 days after injection.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation application of U.S.
patent application Ser. No. 15/975,577, filed May 9, 2018, which is
a divisional application of U.S. patent application Ser. No.
14/222,082, filed Mar. 21, 2014, now issued U.S. Pat. No.
9,987,233, which claims the benefit under 35 U.S.C. .sctn. 119(e)
of U.S. Provisional Patent Application No. 61/804,185, filed Mar.
21, 2013. These applications are incorporated herein by reference
in their entireties.
BACKGROUND
Technical Field
[0002] This disclosure relates to an injectable sustained release
composition and a method of delivery of the same to reduce
inflammation and to treat pain in joints, including pain caused by
inflammatory diseases such as osteoarthritis or rheumatoid
arthritis.
Description of the Related Art
[0003] Arthritis i.e., inflammation in the joints, consists of more
than 100 different conditions which range from relatively mild
forms of tendinitis and bursitis to crippling systemic forms, such
as rheumatoid arthritis. It includes pain syndromes such as
fibromyalgia and arthritis-related disorders, such as systemic
lupus erythematosus, that involve every part of the body.
[0004] Generally, there are two types of arthritis: [0005]
Rheumatoid arthritis ("RA") and related diseases, which are
immune-mediated systemic inflammatory joint diseases. [0006]
Osteoarthritis ("OA"), which is a degenerative joint disease, the
onset of which is typically mediated by previous joint injury or
other factors.
[0007] The common denominator for all of these arthritic
conditions, including RA and OA is joint and musculoskeletal pain.
Often this pain is a result of inflammation of the joint lining
which is the body's natural response to injury.
[0008] Such inflammation and pain can prevent the normal use and
function of the joint. Pain and disability from arthritis, joint
degeneration, and surgery are generally treated by a combination of
oral medications or intra-articular injections of steroid compounds
designed to reduce inflammation. In addition, other compositions,
such as hyaluronic acid products, have been injected to provide
visco-supplementation. A distinct benefit of a corticosteroid
injection is that the relief of localized inflammation in a
particular body area is more rapid and powerful than what can be
achieved with traditional anti-inflammatory oral medications, such
as aspirin. A single injection also can avoid certain side effects
that can accompany multiple doses of oral anti-inflammatory
medications, notably irritation of the stomach. Injections can be
administered easily in a doctor's office. Other advantages include
the rapid onset of the medication's action. Unfortunately,
injections also have some systemic side effects or are not
effective for extended periods of time.
[0009] Short-term complications are uncommon. Long-term risks of
corticosteroid injections depend on the dose and frequency of the
injections. With higher doses and frequent administration,
potential side effects include thinning of the skin, easy bruising,
weight gain, puffiness of the face, acne (steroid acne), elevation
of blood pressure, cataract formation, thinning of the bones
(osteoporosis), and a rare but serious type of damage to the bones
of the large joints (avascular necrosis). Furthermore, there is an
interdependent feedback mechanism between the hypothalamus, which
is responsible for secretion of corticotrophin-releasing factor,
the pituitary gland, which is responsible for secretion of
adrenocorticotropic hormone, and the adrenal cortex, which secretes
cortisol, termed the hypothalamic-pituitary-adrenal (HPA) axis. The
HPA axis may be suppressed by the administration of
corticosteroids, leading to a variety of unwanted side effects.
[0010] Accordingly, there is a medical need to extend the local
duration of action of corticosteroids, while reducing the systemic
side effects associated with that administration. In addition,
there is a need for sustained local treatment of pain and
inflammation, such as joint pain, with corticosteroids that results
in clinically insignificant or no measurable HPA axis suppression.
In addition, there is a medical need to slow, arrest, reverse or
otherwise inhibit structural damage to tissues caused by
inflammatory diseases such as damage to articular tissues resulting
from osteoarthritis or rheumatoid arthritis.
BRIEF SUMMARY
[0011] Described herein are pharmaceutical compositions, injectable
dosage forms and method of using the same for treating inflammation
and/or manage pain in a body compartment, such as a joint space, an
epidural space, a vitreous body of an eye, a surgically created
space, or a space adjacent to an implant.
[0012] One embodiment provides a pharmaceutical composition,
comprising: a plurality of microparticles, the microparticle
including: (1) a crystalline drug core of more than 70% by weight
of the microparticle, the crystalline drug core including one or
more crystals of fluticasone or a pharmaceutically acceptable salt
or ester thereof; and (2) a polymeric shell encapsulating the
crystalline drug core, the polymeric shell being in contact but
immiscible with the crystalline drug core, wherein said
microparticles when dissolution tested using United States
Pharmacopoeia Type II apparatus exhibit a dissolution half-life of
12-20 hours, wherein the dissolution conditions are: 3 milligrams
of microparticles in 200 milliliters of dissolution medium of 70%
v/v methanol and 30% v/v of water at 25.degree. C.
[0013] A further embodiment provides a pharmaceutical composition,
comprising: a plurality of microparticles, the microparticle
including: (1) a crystalline drug core of more than 70% by weight
of the microparticle, the crystalline drug core including one or
more crystals of fluticasone or a pharmaceutically acceptable salt
or ester thereof; and (2) a polymeric shell encapsulating the
crystalline drug core, the polymeric shell being in contact but
immiscible with the crystalline drug core, wherein the
microparticles are heat treated within a temperature range of
210-230.degree. C. for at least one hour.
[0014] Yet another embodiment provides a unit dosage form of a
corticosteroid for injecting into a body compartment, comprising: a
plurality of microparticles, the microparticle including: (1) a
crystalline drug core of more than 70% by weight of the
microparticle; and (2) a polymeric shell encapsulating the
crystalline drug core, wherein the crystalline drug core includes
one or more crystals of a corticosteroid selected from fluticasone,
fluticasone furoate, and fluticasone propionate, and the polymeric
shell is in contact but immiscible with the crystalline drug core,
wherein the unit dosage form is capable of sustained-release of the
corticosteroid over a period of 2-12 months while maintaining a
minimum therapeutically effective concentration of the
corticosteroid within the body compartment.
[0015] Yet a further embodiment provides a method of decreasing
inflammation or managing pain in a patient in need thereof
comprising administering to the patient, via injection to a body
compartment, a therapeutically effective amount of a pharmaceutical
composition for sustained release of a corticosteroid wherein the
pharmaceutical composition comprises a plurality of microparticles
and a pharmaceutically acceptable vehicle, the microparticle
including: (1) a crystalline drug core of more than 70% by weight
of the microparticle; and (2) a polymeric shell encapsulating the
crystalline drug core, and wherein the crystalline drug core
includes one or more crystals of fluticasone or a pharmaceutically
acceptable salt or ester thereof, and the polymeric shell is in
contact but immiscible with the crystalline drug core.
[0016] A further embodiment provides a method for forming coated
microparticles, comprising: providing a crystalline drug core
including one or more crystals of a corticosteroid, forming a
polymeric shell by coating one or more coats of a polymeric
solution having a biodegradable polymer and a solvent; allowing the
solvent to dry to provide coated microparticles; and heating the
coated microparticles at 210-230.degree. C. for at least one
hour.
[0017] Yet another embodiment provides a method of decreasing
inflammation or managing pain in a patient in need thereof
comprising: administering to the patient, via a single injection to
a body compartment, a unit dosage form for sustained release of a
corticosteroid wherein the unit dosage form comprises a plurality
of microparticles and a pharmaceutically acceptable vehicle,
wherein the crystalline drug core includes one or more crystals of
a corticosteroid selected from fluticasone, fluticasone furoate,
and fluticasone propionate, and the polymeric shell is in contact
but immiscible with the crystalline drug core, and wherein,
following the single injection, the corticosteroid is released over
a period of 2-12 months while maintaining a minimum therapeutically
effective concentration of the corticosteroid within the body
compartment.
[0018] The present disclosure further provides a corticosteroid
which is administered locally as a sustained release dosage form
(with or without an immediate release component) that results in
efficacy accompanied by clinically insignificant or no measurable
effect on endogenous cortisol production.
[0019] The present disclosure further provides a membrane based,
diffusion-driven release mechanism with drug particle sizing large
enough to allow high drug loading, but small enough to be injected
intra-articularly.
[0020] The present disclosure further provides a use of an
intra-articularly injected, therapeutically effective amount of a
pharmaceutical preparation for sustained release of a
corticosteroid selected from the group consisting of fluticasone,
fluticasone furoate, and fluticasone propionate, comprising a
multiplicity of coated microparticles, said coated microparticles
having a mean diameter in a range of 50 .mu.m to 400 .mu.m and
wherein the microparticles are particles comprised of greater than
70% corticosteroid by weight, to decrease inflammation and to
reduce pain in a patient.
[0021] As provided herein, corticosteroids ("drug" or "therapeutic
agent") are coated with a semi-permeable polymeric shell and
injected into the joint. Water then diffuses through the polymer
and dissolves the drug core (D) creating a saturated solution
inside the membrane (C) and essentially sink conditions outside the
particle (c). This concentration gradient drives a constant (zero
order) release of drug from the drug particle as long as there is
some drug core remaining to maintain a saturated solution. The
period of release can be tuned by altering the permeability of the
polymer coating.
[0022] The present disclosure further relates to the delivery of
compositions to reduce inflammation and to treat pain in joints,
including pain caused by inflammatory diseases such as
osteoarthritis or rheumatoid arthritis and to slow, arrest or
reverse structural damage to tissues caused by an inflammatory
disease, for example damage to articular and/or peri-articular
tissues caused by osteoarthritis or rheumatoid arthritis.
[0023] By way of the method of the present disclosure, there is
provided a means to reduce morbidity due to arthritis by employing
and administering to a patient a long-lasting injectable,
intra-articular drug delivery composition. While intra-articular
steroids have been a mainstay of treatment for arthritis for more
than 50 years, for many patients, multiple steroid injections are
necessary with attendant risks and side effects. There is provided
herein a platform and method to overcome these side effects via a
sustained release delivery method, which can provide pseudo-zero
order release, without an initial burst, on the order of months for
low solubility steroids. An intra-articular injectable formulation
for this use and with these properties has never been described in
the literature.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
[0024] The following figures set forth embodiments in which like
reference numerals denote like parts. Embodiments are illustrated
by way of example and not by way of limitation in all of the
accompanying figures wherein:
[0025] FIG. 1 shows schematically a microparticle of core/shell
morphology.
[0026] FIG. 2 shows the in vitro release profiles of fluticasone
propionate as uncoated powder, uncoated crystal and coated
crystal.
[0027] FIG. 3A shows the release profiles of fluticasone propionate
microparticles having undergone heat-treatment at various
temperatures.
[0028] FIG. 3B shows the release half-lives of fluticasone
propionate microparticles having undergone heat-treatment at
various temperatures.
[0029] FIGS. 4A and 4B show the particle size distribution of the
fluticasone propionate microparticles as compared to particle size
distribution of triamcinolone hexacetonide (TA) (Kenalog.TM.)
[0030] FIG. 5 is a graph showing the relative amounts of
fluticasone propionate and PVA in microparticles by .sup.1HNMR
analysis.
[0031] FIG. 6 is a graph showing dissolution profiles of
triamcinolone hexacetonide (TA) as compared to sustained release
(SR) formulations of fluticasone propionate (FP) according to
embodiments of this disclosure.
[0032] FIG. 7 is a graph showing plasma fluticasone (FP) levels,
synovial fluid FP levels after injection of 20 mg formulation into
knee joint of sheep as compared to intra-articular pharmacokinetics
of triamcinolone hexacetonide (40 mg) from human subjects.
[0033] FIGS. 8A, 8B and 8C demonstrate the results of a
histological examination of the injected joints of sheep showing no
abnormalities.
[0034] FIG. 9 shows the local concentrations in tissue and synovial
fluid of knee joints of dogs for a period of 60 days following a
single injection of a low dose fluticasone propionate. The plasma
concentrations were too low to detect.
[0035] FIG. 10 shows the local concentrations in tissue and
synovial fluid of knee joints of dogs, as well as the plasma
concentrations, for a period of 60 days following a single
injection of a high dose fluticasone propionate.
[0036] FIG. 11 shows the plasma concentrations of fluticasone
propionate following injections to the knee joints of sheep as
compared to those of dogs. The microparticles for each injection
had undergone different heat-treatments prior to being formulated
into injectable compositions.
[0037] FIG. 12 shows the plasma concentrations of fluticasone
propionate in the knee joints of dogs over a period of 45 hours
following a single injection. The pharmacokinetic (PK) curve
indicates a lack of initial burst.
DETAILED DESCRIPTION
[0038] Described herein are pharmaceutical compositions, injectable
dosage forms and method of using the same for treating inflammation
and/or manage pain in a body compartment, such as a joint space, an
epidural space, a vitreous body of an eye, a surgically created
space, or a space adjacent to an implant. The pharmaceutical
composition includes a plurality of microparticles in core/shell
morphology. In particular, the microparticle includes a crystalline
drug core of a corticosteroid and a polymeric shell encapsulating
the crystalline drug core. As discussed in further detail herein,
the injectable microparticles are characterized with high
drug-loading, narrow size distribution and a sustained release
profile of pseudo zero-order release over a period of 2-12 months
within a body compartment, e.g., a joint.
[0039] Several studies have confirmed that the efficacy of
intra-articular corticosteroids is directly related to their
intra-articular residence time. Caldwell J R. Intra-articular
corticosteroids. Guide to selection and indications for use. Drugs
52(4):507-514, 1996. It has been surprisingly found that when a
direct injection of the pharmaceutical composition or dosage form
is made to a body compartment, e.g., an intra-articular space, an
epidural space or within the vitreous of the eye, there is an
unexpected, long-term sustained release of the corticosteroid with
minimal systemic impact.
[0040] The sustained release delivery mechanism is based on
dissolution. While not wishing to be bound by any specific
mechanism of action, it has been found that when crystalline
corticosteroid drug particles coated with semi-permeable polymeric
shells are injected into a body compartment, e.g.,
intra-articularly, water from the body compartment diffuses through
the polymeric shell and partially dissolves the crystal drug core.
As a result, a saturated solution of the drug is formed inside the
polymeric shell. Since there are essentially sink conditions in the
fluid (e.g., synovia when the body compartment is a joint) in which
the microparticles are injected and reside, a concentration
gradient is created which continuously drives the corticosteroid
drug out of the microparticles and into the surrounding fluid. As
long as there is some drug core remaining to maintain a saturated
solution within the polymeric shell, a constant (i.e., zero order
or pseudo-zero order) release of the drug from the coated
microparticles is obtained.
[0041] Also disclosed herein is a method for reducing inflammation
or managing pain, e.g. due to arthritis, by administering an
injectable dosage form to a body compartment (e.g., intra-articular
injection). Advantageously, the release is highly localized within
the local tissue or fluid medium of the body compartment (e.g.,
synovium of synovial fluid) to ensure a long-acting local
therapeutic level, while maintaining a low or undetectable systemic
level of the corticosteroid.
Definitions
[0042] The articles "a" and "an" are used herein to refer to one or
to more than one (i.e., to at least one) of the grammatical object
of the article. By way of example, "an element" means one element
or more than one element.
[0043] The term "plurality" means "two or more", unless expressly
specified otherwise. For example, "plurality" may simply refer to a
multiplicity of microparticles (two or more) or an entire
population of microparticles in a given composition or dosage form,
e.g., for purpose of calculating the size distribution of the
microparticles.
[0044] As used herein, unless specifically indicated otherwise, the
word "or" means "either/or," but is not limited to "either/or."
Instead, "or" may also mean "and/or."
[0045] When used with respect to a therapeutic agent or a drug
(e.g., a corticosteroids), the terms "sustained release" or
"extended release" are used interchangeably. Sustained release
refers to continuously releasing the therapeutic agent over an
extended period of time after administration of a single dose, thus
providing a prolonged therapeutic effect throughout the release
period.
[0046] "Sustained release" is in contrast to a bolus type
administration in which the entire amount of the active
agent/substance is made biologically available at one time.
Nevertheless, "sustained release" may include an initial faster
release followed by a longer, extended period of slower release. As
discussed in further detail below, the construction of the
microparticles makes it possible to minimize the initial faster
release (e.g., a burst release) and prolong the extended release
period to achieve a profile of near constant release that is
irrespective of the drug concentration (i.e., a zero-order or
pseudo zero-order release).
[0047] Not all non-zero release is within the meaning of "sustained
release." Rather, "sustained release" should provide at least a
minimum therapeutically effective amount (as defined herein) of the
corticosteroids during the release period. It should be understood
that the minimum therapeutically effective amount of corticosteroid
depends on the severity of the inflammation and/or pain to be
addressed.
[0048] "Sustained release period" refers to the entire period of
release during which a local concentration of the corticosteroid
drug is maintained at or above a minimum therapeutically effective
amount. The desired sustained-release period can, of course, vary
with the disease or condition being treated, the nature of the
corticosteroid, and the condition of the particular patient to be
treated. Thus, the desired sustained-release period can be
determined by the attending physician.
[0049] "Local concentration" refers to the concentration of the
corticosteroid drug within a body compartment (as defined herein),
including the concentration in the tissue or fluid of the body
compartment.
[0050] "Plasma concentration" refers to the concentration of the
corticosteroid drug in the plasma or serum. The injectable
microparticles are capable of highly localized release during a
prolonged period while maintaining a low plasma concentration,
e.g., sufficiently low to minimize HPA axis suppression during the
sustained release period. Plasma concentration below 75 pg/mL is
considered below quantifiable limits (BQL), below 30 pg/mL is
considered undetectable.
[0051] Within the scope of the present disclosure, sustained
release of the corticosteroid is achieved due to the unique
structure of the microparticles, which are in core/shell
morphology. In particular, a crystalline drug core of a
corticosteroid is encapsulated by a polymeric shell composed of one
or more polymeric coatings, each permeable to the corticosteroid.
In a preferred embodiment, all layers comprise the same polymer. In
other embodiments, two to four layers of the polymer are coated on
the corticosteroid, with each layer incrementally slowing the
release of the active ingredient and collectively providing the
desired sustained release. Furthermore, sustained release of the
corticosteroid is achieved by tailoring this delivery platform to
the aqueous or sink environment of the body compartment (e.g.,
synovium).
[0052] As used herein, a "patient," or "subject," to be treated by
the methods according to various embodiments may mean either a
human or a non-human animal, such as primates, mammals, and
vertebrates.
[0053] The phrase "therapeutically effective amount" refers to an
amount of a therapeutic agent that, when delivered to a body
compartment (e.g., intra-articularly) in the form of the coated
microparticles as defined herein, produces a degree of reduced
inflammation or pain in the body compartment (e.g., a joint) in a
patient (at a reasonable benefit/risk ratio applicable to any
medical treatment). The effective amount of the therapeutic agent
may vary depending on such factors as the type and severity of
arthritis being treated, its advancement, the degree of pain to
which patient is subject, the particular microparticle being
administered, the active agent and/or the size/age/gender of the
subject. One of ordinary skill in the art may empirically determine
the effective amount of a particular therapeutic agent according to
known methods in the art. Unless specified otherwise,
"therapeutically effective amount" refers to the amount of the
therapeutic agent localized within the body compartment.
[0054] "Minimum therapeutically effective amount" is the least
amount of the therapeutic agent that is capable of producing a
therapeutic effect (e.g., pain reduction or anti-inflammation).
[0055] "EC50" is the concentration of the therapeutic agent that
provides 50% of the maximal effect, e.g., in reducing inflammation
or pain.
[0056] "Unit dosage form" refers to physically discrete units
(e.g., loaded syringe cylinders) suitable as unitary dosages for
human subjects, each unit containing a predetermined quantity of
the therapeutic agent in association with a pharmaceutical
acceptable vehicle. The quantity of the therapeutic agent is
calculated to produce the desired therapeutic effect for a desired
period of time.
[0057] The term "treating" is art-recognized and includes treating
the disease or condition by ameliorating at least one symptom of
the particular disease or condition, even if the underlying
pathophysiology is not affected. "Body compartment" refers to a
space or cavity within the body of a vertebrate (including human)
that is accessible by injection. Typically, the body compartment is
at least semi-enclosed or fully enclosed by hard or soft tissue
(e.g., bones, membranes, ligamentous structure) that defines the
space. Soft tissue is typically present and may have various
degrees of vascularization. The body compartment typically contains
a fluid, such as the synovial fluid in the joints, spinal fluid in
the epidural and the vitreous humour in the vitreous body of the
eye. The fluid may or may not communicate with the outside of the
body compartment. More specifically, the body compartment may be
naturally occurring anatomical space such as a synovial joint, an
epidural space or a vitreous body of an eye. In addition, the body
compartment may also be a surgically created space (e.g., a pocket
for inserting an implanted device, soft tissue implant such as
breast implant, and the like) or any space near the implant that
can be accessed through injection.
[0058] The term "synovial joint" refers to a moveable articulation
of two or more bones. The articulation is defined by a synovial
cavity, which contains a volume of synovial fluid, is lined with a
synovial membrane, and is surrounded by a fibrous capsule. The
opposing bone surfaces are each covered with a layer of cartilage.
The cartilage and synovial fluid reduce friction between the
articulating bone surfaces and enable smooth movements. Synovial
joints can be further distinguished by their shape, which controls
the movements they allow. For example, hinge joints act like the
hinge on a door, allowing flexion and extension in just one plane.
An example is the elbow between the humerus and the ulna. Ball and
socket joints, such as the hip, allow movement in several planes
simultaneously. Condyloid (or ellipsoid) joints, such as the knee,
permit motion in more than one plane in some positions but not
others. For example, no rotation is possible in the extended knee,
but some rotation is possible when the knee is flexed. Pivot
joints, such as the elbow (between the radius and the ulna), allow
one bone to rotate around another. Saddle joints, such as at the
thumb (between the metacarpal and carpal) are so named because of
their saddle shape, and allow movement in a variety of directions.
Finally, gliding joints, such as in the carpals of the wrist, allow
a wide variety of movement, but not much distance.
[0059] Synovial joints include, but are not limited to, shoulder
(glenohumeral and acromioclavicular), elbow (ulno-humeral,
radio-capitellar and proximal radioulnar), forearm (radioulnar,
radiocarpal, ulnocarpal), wrist (distal radioulnar, radio-carpal,
ulno-carpal, mid carpal), hand (carpo-metacarpal,
metocarpophalangeal, interphalangeal), spine (intervertebral), hip,
knee, ankle (tibiotalar, tibiofibular), and foot (talocalcaneal,
talonavicular, intertarsal, tarso-metatarsal,
metatarsal-phalangeal, interphalangeal).
[0060] "Intra-articular" and "intravitreous" are used herein
interchangeably to mean within the vitreous humour of the eye.
[0061] As used herein, the term "microparticle" means a particle
having mean dimension less than 1 mm. Although the microparticles
are substantially spherical in some embodiments, the microparticles
can be any solid geometric shape which is not inconsistent with the
principles of the disclosure, including, without limitation,
needles, ellipsoids, cylinders, polyhedrons and irregular
shapes.
[0062] Microparticles are coated crystalline drug particles. As
used herein, a microparticle has a "core/shell" morphology, shown
schematically in FIG. 1, in which the drug core (10) is
encapsulated by a polymeric shell (20), the polymeric shell may
include one or more thin coatings of the same or different polymers
(two coatings, 25 and 30, are shown). Importantly, the polymeric
shell (20) is formed of polymer coatings that are not miscible with
the drug core, thus, the interface (40) between the drug core and
the polymeric shell is sharp with minimal amounts of drug or
polymer (e.g., less than 5%, or less than 1% or less than 0.5% of
the total weight of either the drug or polymer shall be mixed).
Because the drug core contains a highly hydrophobic corticosteroid
drug, the polymeric shell includes at least one hydrophilic
polymer. Although the polymeric shell may be ultimately degraded,
it should maintain its structural integrity throughout the
sustained release period, thus retaining an environment for the
dissolving drug core to form a saturated solution.
[0063] As used herein, the term "active pharmaceutical ingredient,"
"therapeutic agent," or drug, means one or more corticosteroids. As
used herein, corticosteroid means fluticasone or a pharmaceutically
acceptable salt or ester thereof. More specifically, the
corticosteroid may be at least one of fluticasone, fluticasone
furoate, and fluticasone propionate, derivatives, or
pharmaceutically acceptable salts or esters thereof.
[0064] As used herein, the terms "crystalline drug core," "core
particle," and "drug core" interchangeably refer to a pre-formed
particle that includes a single crystal or multiple crystals of the
drug. The drug core is encapsulated by a polymeric shell. The core
particle can further comprise other compounds, including, without
limitation, binders, buffers, antioxidants, excipients, and
additional active pharmaceutical ingredients. The core particle can
be a single large crystal, a multiplicity of crystals, or mixtures
of the above. In a preferred embodiment, the drug core is
substantially pure drug (i.e., at least 90%, or at least 95% or at
least 98% of the entire weight of the drug core is the drug). In a
preferred embodiment, the drug core is 100% crystalline drug.
[0065] As used herein, "polymeric shell" includes one or more
polymeric coatings. "Polymeric coating" means a thin layer of
linear, branched or cross-linked macromolecules that has a
continuous surface surrounding the crystalline drug core. Referring
to FIG. 1, the polymeric coatings (25 and 30) are sequentially and
concentrically coated on the drug core (20). Although the drug core
(20) and the immediate adjacent polymeric coating (25) should be
immiscible, the polymeric coatings (25 and 30) themselves may be in
intimate contact with each other, allowing for certain degrees of
miscibility at the interface (50) between adjacent coatings in
order to form a polymeric shell (20) of a cohesive structure that
affords structural integrity during the sustained release period.
The polymeric shell must substantially surround or envelope the
core particles.
[0066] "Coating solution" refers to a solution of pre-formed
polymers (e.g., commercially available polymers) and is suitable
for coating the drug core according to known methods of the art,
e.g. fluidized bed coating.
[0067] As used herein, the term "permeable" means allowing the
passage of molecules of the therapeutic agent by diffusion but not
by fluid flow.
[0068] As used herein, the term "semi-permeable" means permeable to
some molecules but not to others. As used herein, semi-permeable
polymeric shell are permeable to at least water and the therapeutic
agent within the coated microparticles of the disclosure.
[0069] "Dissolution half-life" is an in vitro measurement of the
dissolution characteristics of the microparticles. Specifically,
the dissolution half-life is the amount of time that is taken for
half of the original loading of the drug in the microparticles to
dissolve and release into a dissolution medium under a specific set
of dissolution conditions. Although carried out in vitro, the
dissolution half-life is nevertheless an art-recognized factor to
consider in predicting in vivo release characteristics and can
represent an accelerated model of the sustained release behavior in
vivo. In particular, dissolution half-life provides a qualitative
tool for predicting in vivo behaviors by comparing the dissolutions
half-lives of various formulations. For instance, formulations that
exhibit a longer dissolution half-life in vitro are expected to
exhibit a longer sustained release period in vivo. Unless specified
otherwise, the dissolution system used for measuring dissolution
half-life the microparticles is USP Type II (paddle).
[0070] "Dissolution profile" is a graphic representation of the
percentage dissolution as measured by time. Besides providing
quantitatively the dissolution amount as a function of time, the
curvature of the profile qualitatively shows the extent of the
initial burst. For example, a sharp rise in the curvature indicates
a faster initial release (burst) when compared with a gentler
rise.
[0071] "Vehicle" refers to a non-toxic carrier, adjuvant, or
solvent into which the microparticles are suspended. The vehicle
does not alter or destroy the pharmacological activity of the
therapeutic agent with which it is formulated. Pharmaceutically
acceptable carriers or vehicles that may be used in the
compositions include, but are not limited to, water, physiological
saline, hyaluronic acid, and the like. As used herein, the term
"biocompatible" means characterized by not causing a toxic,
injurious or immunological response when brought into contact with
living tissue, particularly human or other mammalian tissue.
[0072] As used herein, the term "biodegradable" means capable of
partially or completely dissolving or decomposing in living tissue,
particularly human or other mammalian tissue. Biodegradable
compounds can be degraded by any mechanism, including, without
limitation, hydrolysis, catalysis and enzymatic action.
[0073] As used herein with respect to polymeric coatings, the term
"substantially degraded" means degraded to the degree that
approximately 50% of the chemical bonds resulting from
polymerization of the polymer-forming solution to form the
polymeric coating have been broken.
[0074] As used herein with respect to the polymeric shell of the
disclosure, the term "structural integrity" means retaining a
continuous surface which is semi-permeable and permits diffusion,
but does not include any discontinuities which permit fluid
flow.
[0075] As used herein, the term "external environment" means the
local area or region of tissue surrounding the coated
microparticles of the disclosure after direct injection into the
body compartment.
[0076] As used herein, the term "saturated" means containing the
maximum concentration of a solute (e.g., an active pharmaceutical
ingredient) that can be dissolved at a given temperature.
[0077] As used herein, the term "substantially insoluble" means
having a solubility of less than 1 part solute per 1000 parts
solvent by weight.
[0078] As used herein, the term "hydrophobic" means having lower
affinity for an aqueous solvent than an organic solvent.
[0079] As used herein, the term "hydrophilic" means having lower
affinity for an organic solvent than an aqueous solvent.
[0080] As used herein, term "pseudo-zero-order kinetics" means
sustained-release of the active pharmaceutical ingredient
(corticosteroid) which exhibits kinetics which is zero-order (i.e.,
independent of concentration) or between zero-order and first-order
(i.e., proportional to concentration) kinetics over the
sustained-release period, where the concentration is based on the
total amount of the active pharmaceutical ingredient contained
within the coated microparticles. In some embodiments, the release
of the active pharmaceutical ingredient exhibits kinetics which
more closely approximate zero-order than first-order kinetics.
[0081] As used herein, the recitation of a numerical range for a
variable is intended to convey that the disclosure may be practiced
with the variable equal to any of the values within that range.
Thus, for a variable which is inherently discrete, the variable can
be equal to any integer value within the numerical range, including
the end-points of the range. Similarly, for a variable which is
inherently continuous, the variable can be equal to any real value
within the numerical range, including the end-points of the range.
As an example, and without limitation, a variable which is
described as having values between 0 and 2 can take the values 0, 1
or 2 if the variable is inherently discrete, and can take the
values 0.0, 0.1, 0.01, 0.001, or any other real values and if the
variable is inherently continuous.
Microparticles
[0082] The microparticles of the core/shell morphology described
herein are constructed to exhibit a sustained release profile
uniquely suited for highly localized, extended delivery of a
corticosteroid drug within a body compartment. In particular, the
microparticle includes (1) a crystalline drug core of more than 70%
by weight of the microparticle, wherein the crystalline drug core
includes one or more crystals of fluticasone or a pharmaceutically
acceptable salt or ester thereof; and (2) a polymeric shell
encapsulating the crystalline drug core, whereby the polymeric
shell is in contact but immiscible with the crystalline drug
core.
[0083] The in vivo sustained release profile is correlatable to the
in vitro dissolution characteristics of the microparticles, which
in turn are determined by, among others, the solubility of the drug
core, the permeability, the level of crosslinking and the rate of
degradation of the polymeric shell. Due to a precision
heat-treatment step in the formation, the microparticles described
herein unexpectedly have a long dissolution half-life of 12-20
hours, when tested using United States Pharmacopoeia Type II
apparatus wherein the dissolution conditions are 3 milligrams of
microparticles in 200 milliliters of dissolution medium of 70% v/v
methanol and 30% v/v of water at 25.degree. C. These features are
discussed in more detail below.
Crystalline Drug Core
[0084] The crystalline drug core according to the embodiments of
this disclosure is a corticosteroid drug. More specifically, the
crystalline drug core comprises at least one of fluticasone, or a
pharmaceutically acceptable salt or ester thereof. More
specifically, the core comprises at least one of fluticasone,
fluticasone furoate, and fluticasone propionate. Most preferably,
the corticosteroid is fluticasone propionate.
[0085] As the preferred system is for formulating corticosteroids,
and as this is a "dissolution based delivery system,"
corticosteroids of relative low solubility are preferred.
Fluticasone in general and fluticasone propionate in particular are
ideal in this regard due to potency and high degree of
insolubility. Johnson M. Development of fluticasone propionate and
comparison with other inhaled corticosteroids. The Journal of
allergy and clinical immunology 101(4 Pt 2):5434-9, 1998.
[0086] The crystalline form of the corticosteroid drug has even
lower solubility than the amorphous form of the same drug,
resulting in a longer dissolution half-life and less initial burst.
Accordingly, the drug core may be a single large crystal or an
aggregation of multiple small crystals. Crystalline drug core
coated with a polymeric shell further extends the period of
dissolution and further minimizes any initial burst.
[0087] The exact anti-inflammatory mechanism of action of
corticosteroids is unknown. However, it is well known that steroids
have many potentially anti-inflammatory actions, and they inhibit
the expression and action of many proinflammatory cytokines.
Brattsand R, et al. Cytokine modulation by glucocorticoids:
mechanisms and actions in cellular studies. Alimentary Pharmacology
& Therapeutics 2:81-90, 1996. Glucocorticoids modulate cytokine
expression by a complex combination of genomic mechanisms, and the
activated glucocorticoid receptor complex can bind to and
inactivate key pro inflammatory transcript factors. In addition,
inflammation can be suppressed via glucocorticoid responsive
elements (GRE) which up-regulate the expression of cytokine
inhibitory proteins. In studies with triggered human blood
mononuclear cells in culture, glucocorticoids strongly diminished
production of the initial phase cytokines IL-1 beta and TNF alpha,
immunomodulatory cytokines IL-2, IL-3, IL-4, IL-6 IL-10, IL-12 and
INF gamma, as well as IL-6, IL-8 and the growth factor GM-CSF. Cato
AC et al. Molecular mechanisms of anti-inflammatory action of
glucocorticoids. Biochemical Society Transactions 18(5):371-378,
1996. In addition to diminishing the production of cytokine,
steroids can also inhibit its subsequent actions. Because cytokines
work in cascades, this means that steroid treatment can block
expression of the subsequent cytokines. This blocked cytokine
activity does not depend on a reduced cytokine receptor expression,
but may be associated with receptor up regulation. Jusko W J.
Pharmacokinetics and receptor-mediated pharmacodynamics of
corticosteroids. Toxicology 102(1-2):189-196, 1995.
[0088] The therapeutic agents are used in amounts that are
therapeutically effective, which varies widely depending largely on
the particular agent being used. The amount of agent incorporated
into the composition also depends upon the desired release profile,
the concentration of the agent required for a biological effect,
and the length of time that the biologically active substance has
to be released for treatment.
[0089] There is no critical upper limit on the amount of
therapeutic agent incorporated except for that of an acceptable
solution or dispersion viscosity to maintain the physical
characteristics desired for the composition. The lower limit of the
agent incorporated into the polymer system is dependent upon the
activity of the corticosteroid and the length of time needed for
treatment. Thus, the amount of the corticosteroid should not be so
small that it fails to produce the desired physiological effect,
nor so large that it is released in an uncontrollable manner.
[0090] A key advantage of the injectable microparticles lies in the
much higher drug loading than previously known drug-loaded
microparticles. In other words, each microparticle has a
comparatively and significantly smaller fraction as the polymeric
shell, and a comparatively and significantly greater fraction as
the corticosteroid core.
[0091] Moreover, the drug core is substantially pure drug as the
drug core is prepared from recrystallized drug in the form of
either a single large crystal or an aggregate of smaller crystals.
Thus, "substantially pure" means at least 90%, or at least 95% or
at least 98%, or 100% of the entire weight of the drug core is the
drug in a crystalline form.
[0092] Thus, in various embodiments, in each microparticle, 70-97%
of the total weight of microparticle is corticosteroid and 3-30% is
polymer. In one embodiment, the drug core is more than 70% of the
total weight of the microparticle and less than 30% of the total
weight of the microparticle is the polymeric shell. In other
embodiments, the drug core is more than 75%, more than 80%, more
than 85%, more than 90% or more than 95% of the total weight of the
microparticle, with the remainder of the microparticle being the
polymeric shell.
Polymeric Shell
[0093] The polymeric shell comprises one or more concentrically or
consecutively coated polymeric coatings of the same or different
polymers. Standard biocompatible and biodegradable polymeric
coatings known in the art can be employed to the extent that they
meet the requirements described above with respect to retaining
permeability and/or structural integrity during the desired
sustained-release period. While the sustained release period is
enhanced within the scope of the disclosure via higher drug loading
and the beneficial and unexpected interaction of the body
compartment (e.g., synovial environment) and the dissolution-based
delivery system described herein, there are additional factors at
play supporting the superior efficacy of the method herein
including, but not limited to: [0094] the degree of solubility of
the corticosteroid [0095] the rate of clearance of the
corticosteroid from the synovium [0096] the size of the core
particle and/or the amount of the corticosteroid initially present
in the core particle [0097] the presence of other compounds within
the core particle that affect the rate of release of the
corticosteroid [0098] the permeability of the polymeric coating(s)
to the corticosteroid [0099] the rate of degradation of the
polymeric coating(s), as well as other factors.
[0100] As is known in the art, both the permeability and
biodegradability of polymeric coatings can be affected by the
choice of polymeric material (e.g., degree of hydrophobicity or
hydrophilicity relative to the corticosteroid; degree of lability
of bonds under physiological conditions), degree of cross-linking
and thickness. For co-polymers, the ratio of the different monomers
also can be varied to affect permeability and biodegradability.
[0101] In preferred embodiments, suitable biocompatible and
biodegradable polymers include polyvinyl alcohol (PVA),
poly(p-xylylene) polymers (trademarked as Parylene.RTM.),
poly(lactic acid) (PLA), poly(glycolic acid) (PGA),
poly(lactic-co-glycolic acid) (PLGA), poly( -caprolactone) (PCL),
poly(valerolactone) (PVL), poly( -decalactone) (PDL),
poly(1,4-dioxane-2,3-dione), poly(1,3-dioxane-2-one),
poly(para-dioxanone) (PDS), poly(hydroxybutyric acid) (PHB),
poly(hydroxyvaleric acid) (PHV), ethylene vinyl acetate (EVA) and
poly(.beta.-malic acid) (PMLA).
[0102] In order to affect permeability and release rates, the
polymeric coatings can optionally be covalently or ionically
cross-linked. For example, monomers can be chosen which include
chemical groups which are capable of forming additional bonds
between monomers, or separate cross-linking agents can be included
in the polymer-forming solutions in addition to the monomers. In
some embodiments, the cross-linking groups are thermally activated,
whereas in other embodiments they are photoactivated, including
photoactivation by visible or ultraviolet radiation. Cross-linking
groups include, without limitation, unsaturated groups such as
vinyl, allyl, cinnamate, acrylate, diacrylate, oligoacrylate,
methacrylate, dimethacrylate, and oligomethoacrylate groups. As
many corticosteroids are hydrophobic, and because it is desirable
to reduce or avoid dissolution of the drug core into the polymeric
shell in order to maintain a sharp interface between the core and
shell, the polymeric shell should include a hydrophilic polymer,
particularly in the coating that is most proximate to the
crystalline core. Examples of hydrophilic polymeric coatings
include, without limitation, poly(vinyl alcohol) (PVA),
poly(ethylene glycol) (PEG), poly(ethylene oxide),
poly(vinylpyrrolidone), poly(ethyloxazoline), or polysaccharides or
carbohydrates such as alkylcelluloses, hydroxyalkylcelluloses,
hyaluronic acid, dextran, heparan sulfate, chondroitin sulfate,
heparin, or alginate, or proteins such as gelatin, collagen,
albumin, ovalbumin, or polyamino acids.
[0103] Additional examples of suitable polymers can be prepared
from monomers selected from the following group: sugar phosphates,
alkylcellulose, hydroxyalkylcelluloses, lactic acid, glycolic acid,
.beta.-propiolactone, .beta.-butyrolactone, .gamma.-butyrolactone,
pivalolactone, .alpha.-hydroxy butyric acid, .alpha.-hydroxyethyl
butyric acid, .alpha.-hydroxy isovaleric acid,
.alpha.-hydroxy-.beta.-methyl valeric acid, .alpha.-hydroxy caproic
acid, .alpha.-hydroxy isocaproic acid, .alpha.-hydroxy heptanic
acid, .alpha.-hydroxy octanic acid, .alpha.-hydroxy decanoic acid,
.alpha.-hydroxy myristic acid, .alpha.-hydroxy stearic acid,
.alpha.-hydroxy lignoceric acid and .beta.-phenol lactic acid.
[0104] Because the crystalline drug core is comprised of at least
70% by weight of the microparticles, the overall sizes of the
microparticles are largely determined by the size of the
crystalline drug core. Typically, the polymeric shell has a
thickness of about less than 12%, or less than 5% or less than 3%
of the total diameter of the microparticle. Likewise, the weight of
the microparticle is also predominately the weight of the
crystalline core, resulting in a high drug loading. In preferred
embodiments, the microparticle comprises 90-98% w/w of crystalline
drug core and 2-10% w/w of polymeric shell.
[0105] In various embodiments, the microparticles have a mean
diameter of between 50 .mu.m and 800 .mu.m, or a mean diameter of
between 60 .mu.m and 250 .mu.m, or a mean diameter of between 80
.mu.m and 150 .mu.m.
[0106] In a preferred embodiment, the mean diameter is 150 .mu.m
with a standard deviation of less than 50% of the mean diameter. In
another preferred embodiment, the mean diameter is 75 .mu.m with a
standard deviation of less than 50% of the mean diameter.
Methods of Forming Microparticles
[0107] Methods of forming polymeric coatings on particles are well
known in the art. For example, standard techniques include solvent
evaporation/extraction techniques, in-water drying techniques (see,
e.g., U.S. Pat. No. 4,994,281), organic phase separation techniques
(see, e.g., U.S. Pat. No. 5,639,480), spray-drying techniques (see,
e.g., U.S. Pat. No. 5,651,990), air suspension techniques, and dip
coating techniques.
[0108] In a most preferred form, the method of forming
microparticles as described in U.S. Patent Publication 2007/003619,
which is fully incorporated herein by reference. The crystalline
drug core is coated with one or more layers of polymeric coatings,
which together form the polymeric shell. For example, in one
aspect, a PVA polymeric coating can be applied using a dip coating
technique. In brief, a 1% coating solution of PVA in water can be
formed by dissolving excess PVA in water at 60.degree. C. for 2 h
(see, e.g., Byron and Dalby (1987), J. Pharm. Sci. 76(1):65-67).
Alternatively, a higher concentration PVA solution (e.g., 3-4%) can
be prepared in a reflux with heating to approximately
90-100.degree. C. After cooling, the microparticles can be added to
the PVA solution and agitated by, for example, swirling or
stirring. The microparticles are then removed from the solution by,
for example, filtration on filter paper with a mesh size
appropriate to the microparticles. Optionally, vacuum-filtration
can be employed to assist in drying. Untreated, PVA polymeric
coatings or films are readily permeable to water and hydrophilic
drugs. Heating of PVA, however, causes an increase in crystallinity
and decrease of permeability of up to 500-fold with increasing
temperatures in the range of 100-250.degree. C. for periods of
0-160 hours (Byron and Dalby (1987), supra). Thus, in some
embodiments, PVA polymeric coatings can be heated to temperatures
between 100.degree. C. and 250.degree. C., between 125.degree. C.
and 175.degree. C., or between 155.degree. C. and 170.degree. C.
for periods between 1 sec. and 160 hours, between 1 min. and 10
hours, or between 5 minutes and 2 hours. Most preferably, heating
is to 220.degree. C. for one hour. Optionally, the coating process
can be repeated several times to build-up a thicker polymeric
coating. Most preferably, 2-5 coatings are applied to achieve a 5%
thickness of coating.
[0109] In one embodiment, the microparticles undergo a precision
heat treatment step at a temperature within the range of
210-230.degree. C. for at least one hour. It is unexpectedly
discovered that the level of crosslinking, and hence permeability,
can be precision controlled by heating the microparticles within
this temperature range. More preferably, the heat treatment step is
carried out at 220.degree. C. for one hour. As discussed in further
detail below in connection with the dissolution characteristics and
Example 6, heat-treated microparticles at a particular temperature
range (210-230.degree. C.) surprisingly attain a level of
crosslinking and permeability that are capable of significantly
enhancing the dissolution half-life.
In Vitro Dissolution Characteristics
[0110] The structure of the microparticles makes it possible for a
highly localized delivery system based on dissolution. Accordingly,
in vitro dissolution characteristics, such as dissolution half-life
are correlatable to the sustained release period in vivo.
[0111] It is important to recognize that dissolutions models are
designed to give an accelerated dissolution as compared to in vivo
release. An IVIVC that mirrored the actual in vivo dissolution
could take months to complete. Nevertheless, an accelerated USP
type II standard dissolution is useful to provide a qualitative
comparison among various formulations and to offer a predicator for
the in vivo release behaviors.
[0112] FIG. 2 shows the effect of the microparticle structures on
dissolution rates. More specifically, FIG. 2 shows the in vitro
release profiles of uncoated fluticasone propionate powder
(amorphous or very small crystals), uncoated fluticasone propionate
crystals and coated fluticasone propionate crystals. The
dissolution profiles clearly show a trend of longer dissolution
half-life and less initial burst in the crystalline drug as
compared to amorphous drug. The trend is more pronounced for the
coated crystalline drug compared to the uncoated crystalline drug.
Additional details of the dissolution conditions are described in
the Example sections.
[0113] The process of forming the microparticles also has a
profound impact on the dissolution characteristics. In particular,
a precision heat-treatment within a narrow temperature range (e.g.,
210-230.degree. C.) unexpectedly provides a significantly enhanced
dissolution half-life when compared to those of microparticles
having undergone heat treatment at temperatures outside of this
range. In a dissolution test using United States Pharmacopoeia Type
II apparatus, wherein the dissolution conditions are 3 milligrams
of microparticles in 200 milliliters of dissolution medium of 70%
methanol and 30% of water at 25.degree. C., the dissolution
profiles of microparticles that have undergone heat treatments at
160.degree. C., 190.degree. C., 220.degree. C. and 250.degree. C.
are shown in FIG. 3A. Microparticles heat-treated at 220.degree. C.
have the slowest and gentlest initial release, as compared to those
of microparticles treated at temperature above or below 220.degree.
C. FIG. 3B shows the dissolution half-lives of the microparticles
of FIG. 3A. As shown, microparticles heat-treated at 220.degree. C.
have a significantly longer dissolution half-life (12-20 hours)
than those of the other microparticles (all less than 8 hours).
[0114] The result indicates that precision thermal processing
(i.e., heating within a narrow range of temperature for a specific
period of time) afford certain structural characteristics
(including, e.g., degrees of crosslinking, crystallinity, porosity
and/or permeability) that are most effective in enhancing the
dissolution half-life, and by extension, the sustained release
period.
In Vivo Release Characteristics
[0115] Preliminary animal studies indicate that corticosteroid
microparticles described herein are capable of highly localized
sustained releasing of the corticosteroid drug within a body
compartment (e.g., an intra-articular space) for 2-12 months after
a single injection, or more typically, for 2-9 months, or for 3-6
months after a single injection. The results are discussed in more
detail in Examples 10-13.
[0116] Even as the local concentrations exceed the EC50 of
corticosteroid, the plasma concentration of the corticosteroid drug
unexpectedly remains much lower than the local concentrations at
any given time during the sustained release period and can be below
quantifiable limit after 7 days. The low plasma concentration
minimizes any clinically significant HPA axis suppression.
[0117] Moreover, the corticosteroid microparticles do not exhibit
any significant initial burst (locally or systemically), unlike
known drug-loaded microparticles.
[0118] The in vivo release characteristics confirm the release
mechanism of pseudo-zero order, by which the corticosteroid drug is
released at a nearly constant rate so long as a saturated solution
can be maintained within the polymeric shell (e.g., for more than
60 days or for more than 90 days, or for more than 180 days),
irrespective of the original drug loading. See also Examples
10-13.
[0119] Further, the in vivo release behaviors are correlatable to
the in vitro dissolution behaviors. In particular, microparticles
that have undergone heat-treatments at different temperatures
(220.degree. C. vs. 130.degree. C.) exhibited in vivo release
behaviors that are consistent with their in vitro dissolutions. See
also, Examples 8 and 11.
Pharmaceutical Composition
[0120] One embodiment provides a pharmaceutical composition
comprising: a plurality of microparticles, the microparticle
including 1) a crystalline drug core of more than 70% by weight of
the microparticle, wherein the crystalline drug core includes one
or more crystals of fluticasone or a pharmaceutically acceptable
salt or ester thereof; and (2) a polymeric shell encapsulating the
crystalline drug core, wherein the polymeric shell is in contact
but immiscible with the crystalline drug core, wherein said
composition when dissolution tested using United States
Pharmacopoeia Type II apparatus exhibits a dissolution half-life of
12-20 hours, wherein the dissolution conditions are 3 milligrams of
microparticles in 200 milliliters of dissolution medium of 70%
methanol and 30% of water at 25.degree. C.
[0121] In a preferred embodiment, the crystalline drug core
comprises at least one of fluticasone, fluticasone furoate, and
fluticasone propionate.
[0122] In certain embodiments, the microparticles have undergone a
heat-treatment step within a temperature range of 210-230.degree.
C.
[0123] In various embodiments, the mean diameters of the
microparticles are in the range between 50 .mu.m and 800 .mu.m, or
in the range between 60 .mu.m and 250 .mu.m, or in the range
between 80 .mu.m and 150 .mu.m.
[0124] In further embodiments, the crystalline drug core is more
than 75%, more than 80%, more than 85%, more than 90% or more than
95% of the total weight of the microparticle, with the remainder of
the microparticles being the polymeric shell.
[0125] In various embodiments, at least 90%, at least 95%, at least
98%, or 100% of the entire weight of the drug core is the drug in a
crystalline form.
[0126] In preferred embodiments, the diameters of the
microparticles in a given pharmaceutical composition may be
tailored or selected to suit a particular route of administration.
Thus, one embodiment provides an injectable composition, in which
more than 90% of the microparticles have diameters in the range of
100-300 .mu.m, which are particularly suitable for an epidural
injection. Another embodiment provides an injectable composition
comprising microparticles in which more than 90% of the
microparticles have diameters in the range of 50-100 .mu.m, which
are particularly suitable for intra-articular or intra-ocular
injection.
[0127] Because the dissolution rate of the crystalline drug is
related to the size of the crystals, i.e., the smaller the
crystals, the higher the initial burst rate (see FIG. 2), it is
preferred that the population of microparticles in a pharmaceutical
composition has a narrow size distribution. Thus, in one
embodiment, the plurality of microparticles in the pharmaceutical
composition have a mean diameter in the range of 50 .mu.m to 300
.mu.m and a standard deviation of less than 50% of the mean
diameter.
[0128] In a preferred embodiment, the mean diameter is 150 .mu.m
with a standard deviation of less than 50% of the mean diameter
(e.g., for epidural injections). In another preferred embodiment,
the mean diameter is 75 .mu.m with a standard deviation of less
than 50% of the mean diameter (e.g., for intra-articular or
intra-ocular injections).
[0129] In a further embodiment, the pharmaceutical composition
further comprises a pharmaceutically acceptable vehicle, in which
the plurality of microparticles is suspended. It is preferred that
the microparticles of corticosteroid are mixed with the vehicle
immediately prior to injection, so there is no time for the
corticosteroid to dissolve into the vehicle and there is no or
substantially no initial burst of drug prior to injection.
Unit Dosage Form
[0130] A unit dosage form is a pharmaceutical composition
(including all the embodiments as described above) having a
predetermined quantity of corticosteroid microparticles which,
after a single injection, provides sustain release of the
corticosteroid for a specified period. The quantity of the
corticosteroid microparticles in a unit dosage will depend upon
several factors including the routes of administration
(intra-articular, intra-epidural, or intra-ocular), the body weight
and the age of the patient, the severity of inflammation or pain,
or the risk of potential side effects considering the general
health status of the person to be treated.
[0131] Advantageously, because the corticosteroid microparticles
described herein are capable of near zero-order release with little
initial burst, the initial loading the drug in the unit dosage form
can be rationally designed according to the desired sustained
release period.
[0132] Thus, one embodiment provides an injectable unit dosage form
of a corticosteroid for injecting into a body compartment, the
injectable unit dosage form comprising: a plurality of
microparticles, the microparticle including (1) a crystalline drug
core of more than 70% by weight of the microparticle; and (2) a
polymeric shell encapsulating the crystalline drug core, wherein
the crystalline drug core includes one or more crystals of a
corticosteroid selected from fluticasone, fluticasone furoate, and
fluticasone propionate, and the polymeric shell is in contact but
immiscible with the crystalline drug core, wherein the injectable
dosage form is capable of sustained-release of the corticosteroid
for a period of 2-20 months while maintaining a minimum
therapeutically effective concentration of the corticosteroid
within the body compartment.
[0133] In a further embodiment, the sustained release period is 2-9
months.
[0134] In a further embodiment, the sustained release period is 3-6
months.
[0135] In other embodiment, the plasma concentration of the
corticosteroid is below quantifiable level after 7 days.
[0136] In various embodiments, the unit dosage form comprises
0.5-20 mg of corticosteroid. In other embodiments, the unit dosage
form comprises 3-20 mg of corticosteroid.
[0137] In various embodiments, the unit dosage form further
comprises a pharmaceutically acceptable vehicle. Preferably, the
vehicle is combined with the corticosteroid microparticles
immediately before injection to avoid dissolution of the drug into
the vehicle. Advantageously, because of the lack of initial burst,
any dissolution of the corticosteroid into the vehicle during
normal handling time in preparation for an injection is
insignificant. In contrast, many known drug-loaded sustained
release formulations are capable of saturating the vehicle during
handling time due to an initial burst.
Methods of Using and Routes of Administration
[0138] The pharmaceutical compositions and dosage forms described
herein are designed to be injected into a body compartment for
highly localized, sustained release of corticosteroid. The body
compartment typically contains soft tissue and/or fluid within an
enclosure or semi-enclosure. The injection is directed to the soft
tissue or the fluid, into which the corticosteroid microparticles
are released. When needed, the injection can be guided by an
imaging system such as an ultrasonic or X-ray device.
[0139] In one embodiment, the injection is administered
intra-articularly for sustained-release of a corticosteroid in the
synovium or synovial fluid.
[0140] In another embodiment, the injection is administered into an
epidural space for sustained-release of a corticosteroid.
[0141] In a further embodiment, the injection is administered
intra-ocularly, or intra-vitreously for sustained-release of a
corticosteroid in the vitreous humour.
[0142] In a further embodiment, the injection is administered to a
surgically created pocket or a natural space near an implant for
sustained-release of a corticosteroid therein for reducing pain
and/or inflammation associated with capsule constriction (e.g.,
following implant) or keloid scar formation.
Diseases that may be Treated Using the Formulations of this
Disclosure
[0143] Various embodiments provide long-acting treatments or
therapies for reducing inflammation and/or pain. Although these
embodiments are exemplified with reference to treat joint pain
associated with osteoarthritis, rheumatoid arthritis and other
joint disorders, it should not be inferred that the disclosure is
only for these uses. Rather, it is contemplated that embodiments of
the present disclosure will be useful for treating other forms of
pain and/or inflammation by administration into articular and
peri-articular spaces, epidural space, vitreous humour of the eye,
or space near an implant having scar tissue formation.
[0144] Thus, the diseases and conditions that may be treated by
intra-articular injection of the pharmaceutical composition and
unit dosage form described herein include, without limitation,
osteoarthritis, rheumatoid arthritis or injury induced arthritis,
Lupus, traumatic arthritis, polymyalgia rheumatica, post-operative
joint pain, facet joint disease/inflammation, tensynovitis,
bursitis, fasciitis, ankylosing spondylitis.
[0145] In other embodiments, the diseases and conditions that may
be treated by an injection to the epidural space include, without
limitation, spinal disc protrusion, spinal nerve inflammation in
cervical, thoracic or lumbar, chronic low back pain from nerve root
compression.
[0146] In other embodiments, the diseases and conditions that may
be treated by an intra-ocular or intra-vitreous injection include,
without limitation, diabetic macular edema and uveitis.
[0147] In other embodiments, the diseases and conditions that may
be treated by an injection into a space near an implant having scar
tissue formation for releasing pain and inflammation are related to
recurrent capsular contractions (e.g., breast implant) and for
keloid scarring control.
[0148] Thus, one embodiment provides a method of treating
inflammation or managing pain in a body compartment of a patient in
need thereof, comprising injecting to the body compartment a
therapeutically effective amount of pharmaceutical composition
having a plurality of microparticles, the microparticle including
1) a crystalline drug core of more than 70% by weight of the
microparticle, wherein the crystalline drug core includes one or
more crystals of fluticasone or a pharmaceutically acceptable salt
or ester thereof; and (2) a polymeric shell encapsulating the
crystalline drug core, wherein the polymeric shell is in contact
but immiscible with the crystalline drug core.
[0149] In a preferred embodiment, the crystalline drug core
comprises at least one of fluticasone, fluticasone furoate, and
fluticasone propionate.
[0150] In various embodiments, the microparticles have undergone a
heat-treatment step within a temperature range of 210-230.degree.
C.
[0151] In various embodiments, the mean diameters of the
microparticles are in the range between 50 .mu.m and 800 .mu.m, or
in the range between 60 .mu.m and 250 .mu.m, or in the range
between 80 .mu.m and 150 .mu.m.
[0152] In preferred embodiments, the diameters of the
microparticles in a given pharmaceutical composition may be
tailored or selected to suit a particular route of administration.
Thus, one embodiment provides an injectable composition, in which
more than 90% of the microparticles have diameters in the range of
100-300 .mu.m, which are particularly suitable for an epidural
injection. Another embodiment provides an injectable composition
comprising microparticles in which more than 90% of the
microparticles have diameters in the range of 50-100 .mu.m, which
are particularly suitable for intra-articular or intra-ocular
injection.
[0153] In further embodiments, the crystalline drug core is
comprised of more than 75%, more than 80%, more than 85%, more than
90% or more than 95% of the total weight of the microparticle,
while the remainder being the polymeric shell.
[0154] In various embodiments, at least 90%, at least 95%, at least
98%, or 100% of the entire weight of the drug core is the drug in a
crystalline form.
[0155] In certain embodiments, said composition when dissolution
tested using United States Pharmacopoeia Type II apparatus exhibits
a dissolution half-life of 12-20 hours, wherein the dissolution
conditions are 3 milligrams of microparticles in 200 milliliters of
dissolution medium of 70% methanol and 30% of water at 25.degree.
C.
[0156] In other embodiments, said composition when dissolution
tested using United States Pharmacopoeia Type II apparatus exhibits
a dissolution half-life of 12-20 hours, wherein the dissolution
conditions are 3 milligrams of microparticles in 200 milliliters of
dissolution medium of 70% methanol and 30% of water at 25.degree.
C.
[0157] A specific embodiment further provides a method of
decreasing inflammation and pain in a patient comprising
administering to the patient in need thereof, via intra-articular
injection, a therapeutically effective amount of a pharmaceutical
preparation for sustained release of a corticosteroid comprising a
multiplicity of coated microparticles, said coated microparticles
having a mean diameter of 50 .mu.m and 350 .mu.m and wherein the
microparticles are particles comprised of greater than 70%
corticosteroid by weight.
[0158] Another embodiment provides a method of treating
inflammation or managing pain in a body compartment of a patient in
need thereof, comprising injecting to the body compartment a single
injection of a unit dosage form having a plurality of
microparticles, the microparticle including (1) a crystalline drug
core of more than 70% by weight of the microparticle; and (2) a
polymeric shell encapsulating the crystalline drug core, wherein
the crystalline drug core includes one or more crystals of a
corticosteroid selected from fluticasone, fluticasone furoate, and
fluticasone propionate, and the polymeric shell is in contact but
immiscible with the crystalline drug core, wherein the injectable
dosage form is capable of sustained-release of the corticosteroid
for a period of 2-12 months while maintaining a minimum
therapeutically effective concentration of the corticosteroid
within the body compartment.
[0159] Additional specific embodiments include: [0160] said
microparticles have a mean diameter of between 50 .mu.m and 800
.mu.m. [0161] said microparticles have a mean diameter of between
60 .mu.m and 250 .mu.m. [0162] said microparticles have a mean
diameter of between 80 .mu.m and 150 .mu.m. [0163] the
corticosteroid is selected from the group consisting of
fluticasone, fluticasone furoate, and fluticasone propionate.
[0164] the corticosteroid is a pharmaceutically acceptable ester
prodrug of fluticasone (fluticasone propionate). [0165] said
preparation is administered at a site permitting direct interaction
between said corticosteroid and an affected joint of said patient.
[0166] sustained release refers to at least three months. [0167]
wherein inflammation and pain is arthritic joint pain. [0168]
wherein said pharmaceutical preparation for sustained release
comprises large particles of substantially pure corticosteroid
coated with at least one biocompatible or bio-erodible polymer.
[0169] which reduces or eliminates an initial corticosteroid drug
burst. [0170] the polymer comprises at least one of polylactic
acid, polyvinyl alcohol and Parylene.TM. [0171] the systemic levels
of fluticasone administered in the method as described herein
produce no clinically significant HPA axis suppression. [0172]
inflammation and pain in a patient is due to at least one of
osteoarthritis, rheumatoid arthritis or injury induced arthritis.
[0173] there is at or near consistent and sustained release of a
corticosteroid. [0174] the disease progression is slowed or halted
due to the maintaining of the constant low level of steroid in the
joint space [0175] the particles of corticosteroid are mixed with
the vehicle immediately prior to injection, so there is no time for
the corticosteroid to dissolve into the vehicle and there is no or
substantially no initial burst of drug. [0176] the present method
has fewer systemic side effects than other therapies
[0177] Within the scope of the present disclosure, the
corticosteroid is selected from the group consisting of
fluticasone, fluticasone furoate, and fluticasone propionate. More
preferably: [0178] the corticosteroid is fluticasone propionate.
[0179] diffusion of said corticosteroid across said first polymeric
coating exhibits pseudo-zero-order kinetics during said
sustained-release period. [0180] said first polymeric coating is
not degraded until AFTER a sustained release period (which is a
point of differentiation as compared to other sustained release
formulations) [0181] said first polymeric coating maintains
structural integrity during said sustained-release period. [0182]
said microparticles have a maximum dimension between 50 .mu.m and
250 .mu.m. [0183] said microparticles have a maximum dimension
between 50 .mu.m and 150 .mu.m. [0184] said corticosteroid is
substantially insoluble in said coating solution. [0185] said
corticosteroid is hydrophobic and said first coating solution is
hydrophilic. [0186] The polymeric shell comprises one or more
polymeric coatings that are the same or different and may comprise
a polymer or co-polymer including at least one monomer selected
from the group consisting of sugar phosphates, alkylcellulose,
hydroxyalkylcelluloses, lactic acid, glycolic acid,
.beta.-propiolactone, .beta.-butyrolactone, .alpha.-butyrolactone,
pivalolactone, .alpha.-hydroxy butyric acid, .alpha.-hydroxyethyl
butyric acid, .alpha.-hydroxy isovaleric acid,
.alpha.-hydroxy-.beta.-methyl valeric acid, .alpha.-hydroxy caproic
acid, .alpha.-hydroxy isocaproic acid, .alpha.-hydroxy heptanic
acid, .alpha.-hydroxy octanic acid, .alpha.-hydroxy decanoic acid,
.alpha.-hydroxy myristic acid, .alpha.-hydroxy stearic acid,
.alpha.-hydroxy lignoceric acid, .beta.-phenol lactic acid,
ethylene vinyl acetate, and vinyl alcohol. [0187] the polymeric
coating is applied to said core particles by an air suspension
technique. [0188] said polymeric coating is applied to said core
particles by a dip coating technique.
[0189] These and other changes can be made to the present systems,
methods and articles in light of the above description. In general,
in the following claims, the terms used should not be construed to
limit the disclosure to the specific embodiments disclosed in the
specification and the claims, but should be construed to include
all possible embodiments along with the full scope of equivalents
to which such claims are entitled. Accordingly, the disclosure is
not limited by the disclosure, but instead its scope is to be
determined entirely by the following claims.
EXAMPLES
Example 1
General Procedure for Preparing Crystalline Drug Core
[0190] To fluticasone propionate (FP) powder (1 g), methanol (100
mL) is added and the suspension heated with stirring until a clear
solution is obtained.
[0191] The flask is left at room temperature over-night resulting
in the formation of needle-shaped crystals. The crystals are
collected using a Buchner funnel and thoroughly oven-dried at
40-50.degree. C. for 2 h. The dry FP particles are added to an
80-170 .mu.m mesh sieve along with a monolayer of glass beads. A
30-60 .mu.m mesh sieve is added below the sieve containing the FP
particles and beads, followed by shaking for 3-4 min. The 80-170
.mu.m mesh sieve is replaced with a clean 80-170 .mu.m mesh sieve,
a 2000 .mu.m mesh sieve added to the top (optional), and the sieve
stack attached to a Buchner funnel. The content of the 80-170 .mu.m
mesh sieve containing the FP particles and beads is gently poured
into the 2000 .mu.m mesh sieve to collect the glass beads and
washed with deionized water (DI-H20) under suction. The 2000 .mu.m
mesh sieve is removed and the content of the 80-150 .mu.m mesh
sieve washed with DI-H.sub.2O under suction. A total of 200-300 mL
of DI-H.sub.2O typically is used. Alternatively, the content of the
sieves may be washed with TWEEN-80 (0.1% w/v) before washing with
water, or the glass beads are replaced by gentle grinding using a
glass rod in a 212 .mu.m mesh sieve. The content of the 80-170
.mu.m and 30-60 .mu.m mesh sieves is separately dried at 40.degree.
C. and the dry material combined for polymer coating.
Example 2
Size Distribution of Crystalline Drug Core
[0192] 1 gram of fluticasone propionate (FP) powder (CAS
80474-14-2) was dissolved in 100 mL of ACS-grade methanol over a
hot plate. The final solution was clear. This solution was cooled
and allowed to rest for 24 h at room temperature. The resulting
crystals were filtered, sieved and collected below 180 pm screens
(-180 .mu.m), cleaned with 0.1% TWEEN-80 aqueous solution, and
washed twice with distilled water and dried at 40.degree. C. for 3
h. 940 mg of fluticasone propionate crystals (94% yield) were
obtained using this procedure. FIGS. 4A and 4B show the mean
particle sizes obtained and size distributions.
[0193] FIG. 4A is a graph representing the particle size
distribution of fluticasone propionate monodisperse distribution
with mean particle size of ca. 110 .mu.M, and the standard
deviation is ca. 41 .mu.M. Particles of these sizes can be injected
easily through 23 g needle (internal diameter 320 .mu.M)
[0194] As a comparison, FIG. 4B is a graph representing the
particle size distribution of Traimcinolone Acetonide
(Kenalog.TM.). The mean particle size is ca. 20 .mu.M. There is a
relatively wide distribution with a second peak at ca. 1 .mu.M. The
standard deviation is about 13 .mu.M. These small particles
contribute to the burst effect seen with this type of formulation
common in the prior art. See also FIG. 6.
Example 3
General Procedure for Coating Crystalline Drug Core
[0195] The dry FP crystals prepared according Example 1 are coated
with polyvinyl alcohol (PVA, 2% w/v in 25% v/v isopropyl alcohol in
DI-H.sub.2O) in a model VFC-LAB Micro benchtop fluidized bed coater
system (Vector Corporation) using the following range of
parameters: [0196] air flow, 50-60 L min.sup.-1; [0197] nozzle air,
5.0-25 psi; [0198] pump speed, 10-35 rpm; [0199] inlet temperature,
99.degree. C.; [0200] exhaust temperature, 35-40.degree. C.; [0201]
spray on/off cycle: 0.1/0.3 min.
[0202] The PVA content is periodically measured by quantitative
.sup.1H nuclear magnetic resonance (NMR) spectroscopy by comparing
the relative signal intensities of the FP and PVA resonances in the
drug product to corresponding signals from calibration standards
(See Example 3). A target final PVA concentration in the drug
product is in the range of 0.1-20% w/w, or preferably 2-10% w/w.
Coating of the particles is continued until the desired amount of
PVA has been achieved. The coated particles are then dried in an
oven at 40.degree. C. for 1 h. The dry, coated particles are sieved
in a sieve stack defined by 150 .mu.m mesh and 53 .mu.m mesh
sieves.
Example 4
NMR Analysis for Determining Drug Content in Microparticles
[0203] NMR analysis was used to determine the amounts of the drug
core and the polymeric shell in microparticles by calibrating with
samples of known quantity of the pure drug.
[0204] The NMR system includes a Bruker Spectrospin 300 MHz
magnet,
[0205] Bruker B-ACS 120 autosampler, Bruker Avance II 300 console,
and a Bruker BBO 300 MHz S1 5 mm with Z gradient probe. A
calibration curve was prepared using five samples of known
fluticasone propionate, and PVA concentrations made in NMR grade
d6-DMSO. Proton (1H) NMR was run on two samples: the first
containing only pure fluticasone propionate and the second
containing PVA-coated fluticasone. Each sample was loaded manually
and spun at 20 Hz inside the magnet. The probe was tuned and
matched for proton (1H) NMR. The magnet was shimmed manually with
the first sample in the magnet. Each sample was integrated for 1.5
hours with 1024 scans. Fluticasone peaks were integrated from 5.5
to 6.35 ppm, and the PVA peak was integrated from 4.15 to 4.7 ppm
(see FIG. 5). Using this method, the finished coated fluticasone
particles were determined to contain 2.1% PVA total weight of
coated particles. Assuming spherical particle shape and mean
particle diameter of 100 .mu.m, this represents a coating thickness
of ca. 7 .mu.m.
Example 5
In Vitro Dissolution Analysis
[0206] To each vessel (1000 mL capacity) of a USP Type II
dissolution system is added the dissolution medium and 3 mg of
PVA-coated FP particles. The dissolution medium typically consists
of 5-90% v/v of an alcohol-water mixture, where the alcohol can be
methanol, ethanol, and isopropanol. The volume of dissolution
medium used is in the 50-750 mL range. The temperature of the
dissolution medium is maintained either at room temperature or at a
temperature in the 5-45.degree. C. range. Aliquots are removed from
the dissolution medium at regular, predetermined time points and
the samples are stored for subsequent analysis, such as with
UV-visible absorption spectroscopy or high performance liquid
chromatography.
[0207] A specific set of dissolution conditions is as follows:
[0208] drug for dissolution: 3 mg PVA-coated FP particles; [0209]
dissolution medium: 200 ml of 70% v/v ethanol and 30% v/v water;
[0210] dissolution temperature: 25.degree. C.
Example 6
Thermal Processing and Effects on Dissolutions
[0211] The coated microparticles prepared according to Example 2
were thermal processed, i.e., heat treated for a specific period of
time. Specifically, the interior of a borosilicate Petri dish was
lined with aluminum foil and a monolayer of PVA-coated FP particles
was spread. The dish was covered with perforated aluminum foil. An
oven was pre-heated to the desired set-point and the samples were
heat-treated for a pre-determined amount of time. The temperature
set-point were 160.degree. C., 190.degree. C., 220.degree. C. and
250.degree. C.
[0212] FIG. 3A shows the dissolution profiles of microparticles
having undergone heat treatments at the above temperatures. The
dissolution conditions are as follows: 3 mg of PVA-coated FP
microparticles were dissolved in a dissolution medium of 200 ml of
70% v/v ethanol and 30% v/v water at 25.degree. C. The resulting
concentration-time data are analyzed (e.g., one phase decay model)
to afford the dissolution half-life (shown in FIG. 3B).
[0213] As shown in FIG. 3A, microparticles heat-treated at
220.degree. C. have the slowest and gentlest initial release, as
compared to those of microparticles treated at temperature above or
below 220.degree. C.
[0214] FIG. 3B shows that the dissolution half-lives of the
microparticles of FIG. 3A. As shown, microparticles heat-treated at
220.degree. C. have a significant longer dissolution half-life
(12-20 hours) that those of the other microparticles (all less than
8 hours).
Example 7
Sustained Release (SR) Formulations for Animal Study (Sheep)
[0215] Dry FP crystals were prepared according to Example 1 and
were coated with polyvinyl alcohol (PVA, 2% w/v in 25% v/v
isopropyl alcohol in DI-H.sub.2O) in a model VFC-LAB Micro bench
top fluidized bed coater system (Vector
[0216] Corporation) using the following range of parameters: air
flow, 50-60 L/min; nozzle air, 23 psi; pump speed, 15 rpm; inlet
temperature, 99.degree. C.; exhaust temperature, 35-40.degree. C.;
spray on/off cycle: 0.1/0.3 min.
[0217] The resulting microparticles were then heat-treated at
130.degree. C. for 3 hours.
[0218] The microparticles have mean diameters in the range of
60-150 .mu.m. The PVA content of the resulting microparticles was
2.4% as analyzed by NMR analysis according to the method described
in Example 4.
Example 8
Sustained Release (SR) Formulations for Animal Study (Dog)
[0219] Dry FP crystals were prepared according to the above
procedures and were coated with polyvinyl alcohol (PVA, 2% w/v in
25% v/v isopropyl alcohol in DI-H.sub.2O) in a model VFC-LAB Micro
benchtop fluidized bed coater system (Vector Corporation) using the
following range of parameters: air flow, 50-60 L/min; nozzle air,
8.0 psi; pump speed, 25 rpm; inlet temperature, 99.degree. C.;
exhaust temperature, 35-40.degree. C.; spray on/off cycle: 0.1/0.3
min.
[0220] The resulting microparticles were then heat-treated at
220.degree. C. for 1.5 hours.
[0221] The microparticles have mean diameters in the range of
60-150 .mu.m. The PVA content of the resulting microparticles was
4.6% as analyzed by NMR analysis according to the method described
in Example 4.
[0222] FIG. 6 shows the dissolutions profiles of the microparticles
prepared by Example 8 compared to the microparticles prepared by
Example 7. In addition, FIG. 6 further shows the dissolution
profiles of another corticosteroid (triamcinolone acetonide) and
fluticasone propionate powder (uncoated, non-crystalline or very
small, less than 10 .mu.m crystals). Both coated FP microparticles
(Examples 7 and 8) exhibit much longer dissolution half-lives and
less initial bursts than the FP powder and triamcinolone acetonide.
In addition, microparticles that have been heat-treated at
220.degree. C. are shown to have even longer dissolution half-life
than microparticles similarly prepared but heat-treated at
130.degree. C. (Example 7).
[0223] The dissolution conditions were as follows: [0224] drug for
dissolution: 3 mg PVA-coated FP particles [0225] dissolution
medium: 200 ml of 70% v/v ethanol and 30% v/v water; [0226]
dissolution temperature: 25.degree. C.
Example 9
Formulation of Suspension/Injectability
[0227] Optimized suspension formulations of coated particles were
obtained using an iterative process, whereby different suspension
solutions at varying concentrations were assessed for their ability
to keep coated particles in suspension. The most homogeneously
distributed formulations were then injected through needle sizes
ranging from 18 to 25 gauge. Particle transfer efficiency was
measured by HPLC. A 1% CMC solution provided the maximum suspension
and a 23 gauge needle provided adequate injection efficiency.
[0228] Sterility. Polymer-coated fluticasone particles were
steam-sterilized (122.degree. C., 16 psi, 30 min) in amber vials.
The sterilization process did not affect the chemical composition
of the formulation according to 1H NMR spectroscopy and HPLC
analysis. See FIG. 5. In vitro studies in 500 mL USP Type II
systems confirmed that the sterile material had the same
fluticasone release profile as the same material prior to
autoclaving.
Example 10
In Vivo Pharmacokinetic (Pk) Studies (Sheep)
[0229] In a non-GLP exploratory study, the local toxicity and drug
concentration levels were evaluated for 3 months in sheep (n=4)
after a single intra-articular injection into the left stifle joint
using a 23G needle of a tuberculin syringe. The injectable dosage
form was 0.5 mL of 20 mg extended release fluticasone propionate
(EP-104) prepared according to Example 7.
[0230] Clinical observations were performed throughout the study,
and histopathology was performed at the end of the study to
evaluate local toxicity. To evaluate fluticasone propionate
concentration levels in treated knees, synovial fluid samples were
collected at designated time points. Blood was collected throughout
the study to determine plasma concentration levels. Plasma
fluticasone levels were measured by HPLC-MS. Mistry N, et al.
Characterisation of impurities in bulk drug batches of fluticasone
propionate using directly coupled HPLC-NMR spectroscopy and
HPLC-MS. Journal of Pharmaceutical and Biomedical Analysis
16(4):697-705, 1997. Mortality, morbidity, and body weights were
also evaluated.
[0231] There were no changes during clinical observations, and no
histopathologic changes occurred in any of the knees after 3
months. There was no mortality or morbidity, and sheep gained
weight throughout the study.
[0232] Fluticasone propionate concentrations were detected in
synovial fluid at 3 months (n=4; 11.51, 9.39, 13.22, and 18.89
ng/mL). Plasma concentration levels were less and declined at a
greater rate than those of synovial fluid
[0233] Fluticasone propionate concentrations in plasma were below
quantifiable limits (BQL) at 0 or below 0.3 ng/mL beginning at Day
70. Plasma and synovial fluid concentrations throughout the study
are provided in FIG. 7.
[0234] Of note is an absence of burst and sustained local
concentrations achieved for the duration of the experiment. The
reported EC50 for fluticasone propionate is 7-30 pg/ml. Mollmann H,
et al. Pharmacokinetic and pharmacodynamic evaluation of
fluticasone propionate after inhaled administration, European
journal of clinical pharmacology February; 53(6):459-67, 1998.
Significantly, after 90 days, the local concentration of FP in the
synovial fluid remained considerable amount (n=4; 11.51, 9.39,
13.22, and 18.89 ng/mL) and above the EC50 level, while the plasma
concentration was no longer detectable (the plasma concentration
became BOL at day 70).
[0235] As a comparison, the release of triamcinolone hexacetonide
(40 mg) from human subjects is also plotted in FIG. 7. Derendorf H,
et al. Pharmacokinetics and pharmacodynamics of glucocorticoid
suspensions after intra-articular administration. Clinical
Pharmacology and Therapeutics March; 39(3):313-7 (1986). As shown,
triamcinolone hexacetonide release shows a significant initial
burst followed by rapid decline. The duration of release is
significant shorter than that of the coated FP microparticles
described herein, despite having a much higher initial dose.
[0236] The shape of the PK curve of the corticosteroid
microparticles is substantially different from that of the
triamcinolone hexacetonide. The slow rise and near constant release
over a period of 60 days confirms the release mechanism of
pseudo-zero order, by which the corticosteroid drug is released at
a nearly constant rate so long as a saturated solution can be
maintained within the polymeric shell (e.g., for 60 days),
irrespective of the original drug loading.
[0237] The animals were euthanized on day 90 and the joints excised
and sent for histology. There were no safety or toxicity issues
noted on clinical examination. Histological examination of the
injected joints showed no abnormalities (FIGS. 8A, 8B, and 8C).
Example 11
In Vivo Pharmacokinetic (Pk) Studies (Dogs)
[0238] Extended release fluticasone propionate formulation
(EP-104IAR) was prepared according to Example 8. The in vivo
release characteristics were evaluated in the knee of Beagle dogs
(n=32) during a 60-day study. Two groups of 16 male and female dogs
were evaluated. Group 1 (n=8 males and 8 females) were administered
a target dose of 0.6 mg EP-104IAR by intra-articular injection (the
low dose group). Group 2 was administered a target dose of 12 mg
EP-104IAR by intra-articular injection (the high dose group).
[0239] Synovial fluid and plasma were collected at 7, 29, 46, and
60 days after injection, and cartilage tissue drug concentrations
and microscopic changes were also evaluated at these time points.
Mortality checks, clinical observations, and body weight
measurements were performed. Blood was collected for plasma
bioanalysis from all surviving animals at pre-dose, and on Days 3,
5, and 7; and twice weekly thereafter until necropsy (including the
day of necropsy). Two animals/sex from each group were euthanized
on Day 7, 29, 46 or 60. Prior to necropsy, synovial fluid was
collected for bioanalysis.
Results:
[0240] In the low dose group, there were no measurable
concentrations of free fluticasone propionate in plasma at any of
the sampling time points, indicating the drug remained in the
joint. See FIG. 9.
[0241] In the high dose group, measurable but low plasma
concentrations occurred on Day 3 after injection and ranged from
0.2 to 0.5 ng/mL. On the other hand, local concentrations of the
drug in the synovial fluid and tissue were significantly higher
throughout the entire period of the study. See FIG. 10.
[0242] The highest concentrations of fluticasone propionate in
synovial fluid generally occurred on Day 7 in both dose groups and
ranged from 3 to 25 ng/mL in the low dose group (FIG. 9) and 179 to
855 ng/mL in the high dose group (FIG. 10). In the low dose group,
measurable fluticasone propionate concentrations in synovial fluid
were detected at Day 60, but concentrations were below the limit of
quantification (1.0 ng/mL) at this collection time point.
Fluticasone propionate concentrations in synovial fluid of high
dose animals at Day 60 were 97 to 209 ng/m L.
Example 12
Comparative Results--Sheep Vs. Dog Studies
[0243] FIG. 6 demonstrates the impact on dissolution
characteristics by a thermal processing step during the
microparticle formation. In particular, microparticles that have
undergone a precision thermal processing step (220.degree. C. for
1.5 hours) exhibited a significantly longer dissolution half-life
than that of microparticles that have undergone a thermal
processing step at a much lower temperature (130.degree. C. for 3
hours). The result indicates that the precision thermal processing
step at 220.degree. C. has caused certain structural changes in the
polymeric shell that in turn altered its permeation
characteristics.
[0244] Microparticles that have undergone different thermal
processing steps were used in the sheep study (heat-treated at
130.degree. C.) and dog study (heat-treated at 220.degree. C.) and
their in vivo sustained release behaviors were discussed in
Examples 9 and 10, respectively.
[0245] FIG. 11 shows the plasma concentrations measured in the
sheep study as compared to those in the dog study. As shown, the
plasma concentrations in the sheep study exhibited much higher
concentrations after 3 days, when compared to those in the dog
study, despite the fact that the sheep received a substantially
lower dose (0.25 mg/kg) than the dogs (1.2 mg/kg). Moreover, the
plasma concentrations in the dogs were largely constant before they
became undetectable. In contrast, the plasma concentrations in the
sheep exhibited more variations over the release period. The
results indicate that the thermal processing step during the
microparticle formation had a significantly impact on the release
behaviors in vivo, much like it did on the dissolution behaviors in
vitro (See Example 8).
Example 13
Lack of Initial Burst
[0246] Fluticasone propionate microparticles were prepared
according to
[0247] Example 8. Microparticles having mean diameters in the range
of 50-100 .mu.m were used to study the plasma pharmacokinetic (PK)
in the first two days following injection. Two groups of dogs (n=3
per group) were injected with a 2 mg dose (low dose) and a 60 mg
dose (high dose), respectively.
[0248] Most sustained release formulations are expected to exhibit
an initial burst or a peak in the plasma within the first 48 hours
following dosing. Unexpectedly, however, the FP sustained release
formation according to an embodiment of this disclosure shows no
initial burst. FIG. 12 shows a complete absence of initial burst or
peak in the first 2 days in the high dose group and all samples
were below limit of quantification (albeit detectable). In the low
dose group only a single sample was detectable, but was below
quantification. Accordingly, the sustained release formulations
described herein are capable of highly localized delivery of a
corticosteroid (e.g., fluticasone propionate) while keeping the
systemic corticosteroid below the level that may result in any
clinically significant HPA axis suppression. Significantly, the
complete absence of an initial burst in even the high dose group
indicates that the in vivo release is following a zero-order or
pseudo-zero order pattern.
[0249] All of the above U.S. patents, U.S. patent application
publications, U.S. patent applications, foreign patents, foreign
patent applications and non-patent publications referred to in this
specification and/or listed in the Application Data Sheet, are
incorporated herein by reference, in their entirety.
* * * * *